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CRYSTAL STRUCTURE OF C-TERMINAL DOMAIN OF ICP27 PROTEIN FROM HSV-1
Structural highlights
FunctionICP27_HHV11 Multifunctional regulator of the expression of viral genes that contributes to the shutoff of host protein synthesis and mediates nuclear export of viral intronless mRNAs. Early in infection, this immediate early (EI) protein mediates the inhibition of cellular splicing. This results in the accumulation of unprocessed 3'end pre-mRNAs which can't be exported from the nucleus. Cellular protein synthesis is thereby shut off early after virus infection. Later in the infection, it helps recruit cellular RNA polymerase II to viral replication sites and promotes the nuclear export of viral intronless mRNAs by interacting with mRNAs and host NXF1/TAP. ICP27 binds to NUP62 which may provide facilitated viral mRNA export and may indirectly compete with some host cell transport receptors for binding and inhibit cellular nucleocytoplasmic transport pathways. Also stimulates translation of viral transcripts. Repression of host gene expression blocks the cell cycle at the G1 phase and prevents apoptosis. Seems to silence the 3' splice site of the promyelocytic leukemia (PML) intron 7a, thereby switching PML isoforms from PML-II to PML-V. This could be linked to the accelerated mRNA export induced by ICP27 which might not provide sufficient time for PML pre-mRNA to be spliced in the nucleus.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedHerpes viruses are nuclear-replicating viruses that have successfully evolved to evade the immune system of humans, establishing life-long infections. ICP27 from herpes simplex virus (HSV) is a multifunctional regulatory protein that is functionally conserved in all known human herpes viruses. It has the potential to interact with an array of cellular proteins as well as intronless viral RNAs. ICP27 plays an essential role in viral transcription, nuclear export of intronless RNAs, translation of viral transcripts and virion host shut-off function. It has also been implicated in several signaling pathways and prevention of apoptosis. Although much is known about its central role in viral replication and infection, very little is known about the structure and mechanistic properties of ICP27 and its homologs. We present the first crystal structure of ICP27 C-terminal domain at 2.0 A resolution. The structure reveals the C-terminal half of ICP27 to have a novel fold consisting of alpha-helices and long loops, along with a unique CHCC-type of zinc-binding motif. The two termini of this domain extend out from the central core and hint to possibilities of making interactions. ICP27 essential domain is capable of forming self-dimers as seen in the structure, which is confirmed by analytical ultracentrifugation study. Preliminary in vitro phosphorylation assays reveal that this domain may be regulated by cellular kinases. IMPORTANCE: ICP27 is a key regulatory protein of the Herpes Simplex Virus and has functional homologs in all known human herpes viruses. Understanding the structure of this protein is a step ahead in deciphering the mechanism by which the virus thrives. In this study, we present the first structure of the C-terminal domain of ICP27 and describe its novel features. We critically analyze the structure and compare our results to the information available form earlier studies. This structure can act as a guide in future experimental designs, and can add to a better understanding of mechanism of ICP27 as well as that of its homologs. Structure of C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus-1.,Patel V, Dahlroth SL, Rajakannan V, Ho HT, Cornvik T, Nordlund P J Virol. 2015 Jun 17. pii: JVI.00441-15. PMID:26085142[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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